Re: Amyotrophic lateral sclerosis and occupational exposure to 2,4-D

Carol J Burns, Epidemiologist

The Dow Chemical Company

We appreciate the interest taken in our study by Dr. Freedman.[1] At the heart of the discussion are the interpretation
of statistical significance in our study,[2] and the lack of statistical significance in others. A critical point in valuing
causation is the weight of the evidence to be placed upon the nonsignificant increase of nonspecific exposures observed in
human studies of amyotrophic lateral sclerosis (ALS) compared to the
weight placed upon controlled animal studies specific to the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D).

I agree with Dr. Freedman that undue reliance upon statistical significance is ill advised. He is correct that the case-control
studies cited in our paper showed elevated odds ratios,[3][4][5][6] but there is no evidence that any subjects were actually
exposed to 2,4-D since the exposures were limited to "pesticides" and "agricultural chemicals" and "herbicides". The cohort
studies examined workers who were definitely exposed to 2,4-D and thus provide a more valid assessment of risk even though
they are less powerful than the case-control studies.[7][8] The cohort studies of 2,4-D do not consistently show increased
risk of ALS.

The associations observed in the case-control studies are clearly unsupported by the experimental studies that have been conducted
on 2,4-D. Environmental causes of ALS remain unknown. If future epidemiological studies investigate the neurotoxicity of herbicides
such as 2,4-D, the researchers must improve upon the status quo of surrogate exposure
information used in case-control studies or perform further studies of the 2,4-D workers. Epidemiologist must make a commitment
to quality exposure assessment of individual pesticides, perhaps coupled with biomonitoring, to address the putative health
concerns associated with pesticides.

Division of Cancer Epidemiology and Genetics, National Cancer Institute

Editor

Burns et al.[1] report a significant excess of deaths due to amyotrophic lateral sclerosis (ALS) in a cohort of Dow employees
potentially exposed to the herbicide 2,4-Dichlorophenoxyacetic (2,4-D), but then argue against the plausibility of a causal
association, concluding that the association "is not consistent with previous human or animal studies".

This conclusion and the authors' characterisation of the relevant epidemiologic studies appear to rely entirely upon statistical
significance, which downplays the importance of their finding. Firstly, the authors state that "cohort studies of people with
exposure to 2,4-D (have not) reported
increased rates of ALS," citing two studies,[2] [3] both of which have limited power to detect the risk of ALS. One of the
two studies assessed risk in a cohort that was quite young with a relatively short follow up,[2] and would therefore be unlikely
to detect an increased risk for a
disease such as ALS, which has a much older median age at onset. Burns et al then go on to state that "exposure to pesticides and agricultural chemicals have shown no significant association in several studies"(emphasis added).[1]

In each of the three case-control studies cited, however, ALS was positively associated with pesticides or agricultural chemicals,
with reported ORs of 1.4,[4] 2.0,[5]
and 3.0,[6] although the associations do not reach statistical significance. Finally, Burns et al refer to a case-control study,[7] which found a significant association between ALS and pesticides, but, they emphasise,
"did not find a significant association of exposure to
herbicides".[1] The association between ALS and herbicide exposure was increased, however, and the lack of statistical significance
reflected, at least in part, small numbers.

None of this is meant to say that the finding of a significant association between ALS and 2,4-D is conclusive.
The finding is, however, consistent with several previous studies and, instead of being played down, warrants serious attention
in future studies.